The compounds of formula I.sub.1 include metronidazole phosphate and its salts which are disclosed in U.S. Pat. No. 4,160,827, which in turn are derivatives of the antibiotic compound metronidazole which is disclosed in U.S. Pat. No. 2,944,061. Furthermore, Belgian Pat. No. 873,973 which is equivalent to U.S. Pat. No. 4,160,827 discloses the use of pyrophosphoryl tetrachloride in a process which phosphorylates metronidazole. However, the process disclosed in the Belgian patent is distinguishable from that of the present invention. Particularly, the crystalline intermediates of the present invention have not previously been known. Therefore, it is now understood that the process conditions of the present invention are not appreciated in the prior art. Numerous advantages accrue from use of the invention process and novel intermediates therein such as purification of metronidazol phosphate and preparation of additional analogs not known in previous processes.
In general, phosphorylations of alcohols with phosphoryl trichloride and pyrophosphoryl tetrachloride are well known. Representative references of such phosphorylations include Koransky, W. et al., "Phosphorylation of Nucleosides with Pyrophosphoryl Chloride", Z. Naturforsch, 17, pp. 291-5 (1962), CA, 57, 12609D (1962); Miki, P. et al., "A Phosphorylation of Steroids and A Dienone-Phenol Rearrangement leading to a Secosteroidal Aldehyde Which Has a Strong Toxicity", Chem. Pharm. Bull., Vol. 22, No. 7, pp. 1439-50 (1974); Cremlyn, R. J. W. et al., "A Simple Phosphorylation Procedure for Cyclic Alcohols", Synthesis, pp. 648-50 (1971). Additionally, hydrolysis of phosphorus dichlorides are also known. For example, see Koransky et al. cited above, as well as, Lacey, et al., "A Simple Synthesis of Choline Alkyl Phosphates", Tetrahedron Letters, Vol. 21, pp. 2017-20 (1980). However, none of the above references teach the phosphorylation of metronidazole or the novel compounds of the present invention.
In addition to the disclosed usages in U.S. Pat. Nos. 2,944,061 and 4,160,827, the use of metronidazole and its analogs as an adjunct to radiation therapy in the treatment of cancer is disclosed by Postescu, I. D. et al., "Characterization of Metronidazole-Phosphate. A Water Soluble Metronidazole Derivative as a Radio Sensitizer of Hypoxy Cells", Strahlentherapie, 155, pp. 358-61 (1979).
Further, background references teaching analogs of metronidazole and their uses are also found in Hoffer, M. et al., "Synthesis and Antiprotozoal Activity of 1-(3-Chloro-2-Hydroxypropyl)-Substituted Nitroimidazoles", J. Medicinal Chemistry, Vol. 17, No. 9, pp. 1019-20 (1974) and Benazet, F. et al., "Chimiotherapie", C. R. Acad. Sc. Paris, 263, Serie D-pp. 609-11 (Aug. 8, 1966).